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METHIMAZOLE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Carbimazole and methimazole are organic thiourea antithyroid drugs included in the chemical class of mercaptoimidazolines. These drugs are also included in a broader chemical group, the thioamide derivatives, which also includes propylthiouracil. This group of drugs acts by blocking the production of thyroid hormones. Carbimazole is a prodrug of methimazole. Carbimazole is rapidly and completely metabolized to methimazole in the body, with the antithyroid activity of carbimazole dependent upon this conversion to methimazole.

Specific Substances

    A) CARBIMAZOLE
    1) 1H-Imidazole-1-carboxylic acid, 2,3-dihydro-3-methyl-2-thioxo, ethyl ester
    2) 4-Imidazoline-1-carboxylic acid, 3-methyl-2-thioxo-,ethyl ester
    3) 3-Methyl-2-thioxo-4-imidazoline-1-carboxylic acid ethyl ester
    4) Ethyl 3-methyl-2-thioxo-4-imidazoline-1-carboxylate
    5) Carbimazolum
    6) Molecular Formula: C7-H10-N2-O2-S
    7) CAS 22232-54-8
    METHIMAZOLE
    1) 1-Methylimidazole-2-thiol
    2) 1-Methyl-2-mercaptoimidazole
    3) 2H-Imidazole-2-thione, 1,3-dihydro-1-methyl-
    4) Imidazole-2-thiol, 1-methyl-
    5) Mercazolylum
    6) Methylmercaptoimidazole
    7) Thiamazole
    8) Thiamazolum
    9) Tiamazol
    10) Molecular Formula: C4-H6-N2-S
    11) CAS 60-56-0

Available Forms Sources

    A) FORMS
    1) Methimazole is available in the United States as 5 mg, 10 mg, 15 mg, and 20 mg tablets (Prod Info methimazole oral tablets, 2008; Prod Info Northyx(R) oral tablets, 2007).
    2) Carbimazole is available in Europe, but not in the United States.
    B) USES
    1) Methimazole is used in the management of hyperthyroidism (Prod Info methimazole oral tablets, 2008; Prod Info Northyx(R) oral tablets, 2007).
    2) Carbimazole is also used in the management of hyperthyroidism. It is almost exclusively used in Great Britain, whereas two other thioamide derivatives, propylthiouracil and methimazole, are used in the US for the treatment of hyperthyroidism. Refer to "Propylthiouracil" document for more information.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Methimazole is used in the management of hyperthyroidism. Carbimazole is a prodrug of methimazole.
    B) PHARMACOLOGY: Methimazole is a thyroid hormone synthesis inhibitor. However, it does not inactivate the existing thyroxine and triiodothyronine stored in the thyroid or in the blood.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Most adverse effects are dose-related and occur within the first 4 to 8 weeks of therapy. Chronic ingestion can result in a variety of immunologic-mediated adverse effects which are not expected to occur in overdose, including leukopenia, agranulocytosis, aplastic anemia, eosinophilia, thrombocytopenia, hypoprothrombinemia, vasculitis, nephritis, lupus-like syndrome, and hepatitis. Skin rashes are common following therapy and may occur secondary to hematologic toxicity during chronic therapy. Other reported adverse effects include nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, myalgia, headache, pruritus, drowsiness, neuritis, edema, jaundice, sialadenopathy, and lymphadenopathy. Fatal hepatic necrosis has been reported.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Hypothyroidism is unlikely to develop after a single acute overdose ingestion. Nausea, vomiting, epigastric distress, headache, fever, joint pain, pruritus, edema, or exfoliative dermatitis may occur following an overdose.
    2) SEVERE TOXICITY: Aplastic anemia, pancytopenia, or agranulocytosis may occur several hours to days after an overdose. Hepatitis, nephrotic syndrome, neuropathies, and CNS stimulation or depression may occur infrequently.
    0.2.20) REPRODUCTIVE
    A) Methimazole is classified as FDA Pregnancy Category D. Methimazole crosses the placental membrane readily and can induce goiter and cretinism in the developing fetus. Congenital defects such as aplasia cutis (manifested by scalp defects), esophageal atresia with tracheoesophageal fistula, and choanal atresia with absent/hypoplastic nipples have occurred rarely in infants exposed to methimazole in utero.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serial CBC with differential with platelet count, renal function, liver enzymes, and thyroid function tests after significant overdose.
    C) Plasma concentrations are not routinely available. Measurement of T3 (triiodothyronine) and reverse T3 (a major metabolite of T4 with no metabolic activity) levels may confirm a history of ingestion, but the clinical significance is unknown.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression.
    E) ANTIDOTE
    1) None.
    F) MYELOSUPPRESSION
    1) Treatment with G-CSF or GM-CSF has been shown to significantly shorten recovery time in patients with methimazole-induced agranulocytosis. Administer colony stimulating factor for severe neutropenia. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes. Sargramostim 250 mcg/meter(2)/day IV over 4 hours. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis, peritoneal dialysis, forced diuresis, or charcoal hemoperfusion have not been shown to be beneficial in methimazole overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with a small inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a large or deliberate overdose, and those who are symptomatic, should be referred to a healthcare facility for evaluation. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication. Early effects of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative.
    J) PHARMACOKINETICS
    1) Tmax: approximately 30 to 60 minutes after 60 mg oral dose. Bioavailability: 80% to 95%. Protein binding: Methimazole is virtually non-protein bound. Vd: 40 L. Metabolism: Carbimazole is rapidly and completely metabolized to methimazole in serum. Methimazole: The major route of metabolism is hepatic. Excretion: About 80% in urine. Less than 10% of methimazole is excreted unchanged in the urine. Elimination half-life: Methimazole: 6.4 to 13.6 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Adverse effects at higher doses (60 mg/day) are common.
    B) THERAPEUTIC DOSE: ADULTS: Initial oral doses range from 15 to 60 mg orally in 3 divided doses every 8 hours daily. Maintenance: 5 to 15 mg orally per day. CHILDREN: Initial oral dose is 0.4 mg/kg/day orally in 3 divided doses every 8 hours daily. Maintenance, one-half of the initial oral dose.

Clinical Effects

Summary Of Exposure

    A) USES: Methimazole is used in the management of hyperthyroidism. Carbimazole is a prodrug of methimazole.
    B) PHARMACOLOGY: Methimazole is a thyroid hormone synthesis inhibitor. However, it does not inactivate the existing thyroxine and triiodothyronine stored in the thyroid or in the blood.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Most adverse effects are dose-related and occur within the first 4 to 8 weeks of therapy. Chronic ingestion can result in a variety of immunologic-mediated adverse effects which are not expected to occur in overdose, including leukopenia, agranulocytosis, aplastic anemia, eosinophilia, thrombocytopenia, hypoprothrombinemia, vasculitis, nephritis, lupus-like syndrome, and hepatitis. Skin rashes are common following therapy and may occur secondary to hematologic toxicity during chronic therapy. Other reported adverse effects include nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, myalgia, headache, pruritus, drowsiness, neuritis, edema, jaundice, sialadenopathy, and lymphadenopathy. Fatal hepatic necrosis has been reported.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Hypothyroidism is unlikely to develop after a single acute overdose ingestion. Nausea, vomiting, epigastric distress, headache, fever, joint pain, pruritus, edema, or exfoliative dermatitis may occur following an overdose.
    2) SEVERE TOXICITY: Aplastic anemia, pancytopenia, or agranulocytosis may occur several hours to days after an overdose. Hepatitis, nephrotic syndrome, neuropathies, and CNS stimulation or depression may occur infrequently.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Drug fever has been described in carbimazole-treated patients (Hardman et al, 1996; Kampmann & Hansen, 1981).
    B) WITH POISONING/EXPOSURE
    1) Fever may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) UVEITIS: Methimazole therapy has uncommonly been reported to be related to the occurrence of T-lymphotropic virus type I-associated uveitis, with vitreous opacities and retinal vasculitis. The exact mechanism of this adverse reaction is unknown (Bartalena et al, 1996).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Hearing loss and tinnitus due to carbimazole hypersensitivity have been reported (Hill et al, 1994).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema may occur following therapeutic use of methimazole (Prod Info TAPAZOLE(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Edema may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Following therapeutic use of carbimazole or methimazole, dizziness, paresthesias, neuritis, drowsiness, and headache have been described occasionally (Prod Info TAPAZOLE(R) oral tablets, 2012; Hardman et al, 1996).
    2) WITH POISONING/EXPOSURE
    a) Headache may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).
    b) Neuropathies and CNS depression or stimulation may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, epigastric distress, loss of taste, and sialadenopathy may occur following therapeutic use of methimazole (Prod Info TAPAZOLE(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, or epigastric distress may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Jaundice, usually cholestatic, has been reported with methimazole and carbimazole. An immune-mediated mechanism rather than a toxic reaction has been proposed. Symptoms may occur following usual doses of the drug for durations of therapy as short as 2 to 4 weeks, but usually occur during the first few months of therapy. In this series, 10 cases of methimazole hepatotoxicity were described, seven of which were confirmed as cholestatic (Vitug & Goldman, 1985).
    b) Liver disease may be characterized by the onset of fever, with or without pruritus, jaundice, dark urine, and light colored stools. Liver function tests reveal elevated total and direct bilirubin levels in association with elevated alkaline phosphatase values. Liver biopsy demonstrates changes consistent with cholestasis and drug induced hepatitis with increased portal eosinophils and neutrophils, and irregular and swollen parenchymal cells. Discontinuation of the drug has been reported to result in resolution of the liver toxicity (Bartalena et al, 1996; Schwab et al, 1996; Mamianetti et al, 1995; Binder & Lang, 1993; Sadoul et al, 1993; Moreno Sanchez et al, 1989; Ozenne et al, 1989; Ayensa et al, 1986; Schmidt et al, 1986; Blom et al, 1985; Wheeler et al, 1985). Acute hepatic failure has been reported (Epeirier et al, 1996; Kang et al, 1990).
    c) An IgG autoantibody linked to LDH has been reported in a patient (Gemma et al, 1992).
    B) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) An acute overdose of these drugs might result in elevated serum hepatic enzyme levels, although this has not yet been reported (Prod Info TAPAZOLE(R) tablets, 2004).
    C) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) A rare case of granulomatous hepatitis has been reported in a patient receiving long-term therapy with methimazole. An iatrogenic etiology based on the presence of eosinophils in granulomas was suggested (Di Gregorio et al, 1990).
    2) WITH POISONING/EXPOSURE
    a) An acute overdose of methimazole might result in hepatitis (Prod Info TAPAZOLE(R) oral tablets, 2012).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) KIDNEY DISEASE
    1) WITH THERAPEUTIC USE
    a) Reversible nephrotic syndrome has been observed in only a very few patients during therapy. It is likely that this is the result of a direct toxic effect on the glomerular basement membrane and epithelial podocytes (Bartalena et al, 1996).
    b) CASE REPORT: A young man with Grave's disease developed nephrotic syndrome while receiving methimazole. Histologic features resembled toxic nephrosis. Methimazole may be a direct glomerular toxin (Reynolds & Bhathena, 1979).
    2) WITH POISONING/EXPOSURE
    a) Nephrotic syndrome may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) AGRANULOCYTOSIS
    1) An estimated occurrence of agranulocytosis due to methimazole therapy is between 0.1% and 1%; it most frequently develops within the first 3 months of therapy. Agranulocytosis, an idiosyncratic reaction, may rarely occur and is suspected to be due to an immune-mediated reaction. A transient granulocytopenia has preceded agranulocytosis. It has been suggested that older patients (greater than 40 years old) and higher doses result in an increased risk of agranulocytosis (Breier et al, 2001; O'Doherty, 1999; Escobar-Morreale et al, 1997; O'Hare & Azher, 1997; Tavintharan et al, 1997; Tamai et al, 1996; Bartalena et al, 1996; Ng, 1995; Magner & Snyder, 1994; Schut et al, 1993; Meletis et al, 1993; Yokoyama & Okamoto, 1992; Biswas et al, 1991; Tuschy & Muhlan, 1991; Tajiri et al, 1990; Werner et al, 1989; Douer & Eisenstein, 1988; Hou & Tsai, 1988; Cooper et al, 1983; Hamada et al, 1981).
    b) PANCYTOPENIA
    1) A rare complication of methimazole therapy is pancytopenia, with hypocellular bone marrow. This may present clinically with sore throat, fever, or abnormal bleeding in association with pancytopenia. The occurrence of aplastic anemia is most likely due to initial drug exposure rather than to a dose dependent mechanism. Evidence favors a humoral, most probably autoimmune mechanism, as the cause of transient bone marrow aplasia. Discontinuing the drug and supportive therapy usually results in resolution of the marrow aplasia within 2 to 5 weeks; granulocyte macrophage colony-stimulating factor therapy has also proved helpful (Breier et al, 2001; O'Doherty, 1999; Escobar-Morreale et al, 1997; Bishara et al, 1996; Lopez-Karpovitch et al, 1992; Biswas et al, 1991; Moreb et al, 1983).
    a) CASE REPORT - A rare case of methimazole-induced bone marrow toxicity resulting in massive plasmocytosis, mimicking multiple myeloma, is reported. The 16-year-old female had been taking methimazole for one month prior to the onset of symptoms of sepsis. A hypocellular-normocellular bone marrow, 98% of plasma cells, was seen on bone marrow aspiration. The patient gradually recovered following discontinuation of methimazole and treatment with G-CSF, steroids, and antibiotics (Breier et al, 2001).
    b) CASE REPORT - Aplastic anemia was associated with methimazole 15 mg/day therapy. The patient developed pancytopenia and resulting Klebsiella pneumonia septicemia. Discontinuation of methimazole resulted in complete blood count recovery after 5 weeks (Biswas et al, 1991).
    2) CASE REPORT - A 74-year-old woman developed aplastic anemia 8 weeks after starting methimazole therapy. On admission, she presented with fever, severe hemorrhagic symptoms, sore throat, difficulty swallowing, ulcers and extensive hemorrhages on the mucous membranes, dyspnea, and weakness. Laboratory data revealed granulocytopenia, thrombocytopenia, anemia, hypoprothrombinemia and septicemia. Physical examination and chest X-ray showed bilateral pneumonia. The patient gradually recovered following discontinuation of methimazole and treatment with recombinant human granulocyte colony-stimulating factor (G-CSF), high-dose corticosteroids, antibiotics, and supportive hemotherapy. On day 25, the patient was discharged in remission (Jakucs & Pocsay, 2006).
    c) LEUKOPENIA
    1) Mild leukopenia is reported in approximately 12% of adult patients and 25% of children treated with methimazole. This effect is generally transient and not associated with an increased risk of infection and is only rarely followed by development of agranulocytosis. Mild leukopenia does not necessitate drug withdrawal (Bartalena et al, 1996).
    2) WITH POISONING/EXPOSURE
    a) Aplastic anemia, pancytopenia, or agranulocytosis may occur several hours to days after an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).
    B) PROTHROMBIN TIME LOW
    1) WITH THERAPEUTIC USE
    a) Rarely, these drugs cause hypoprothrombinemia following therapeutic dosing (Lipsky & Gallego, 1988).
    C) LYMPHADENOPATHY
    1) WITH THERAPEUTIC USE
    a) Lymphadenopathy may occur following therapeutic use of methimazole (Prod Info TAPAZOLE(R) oral tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rash with urticaria and pruritus may commonly occur following therapy with these drugs, especially with higher doses. Maculopapular rashes are generally transient and subside spontaneously. Onset is variable; may occur at any time during treatment or upon re-exposure (Bartalena et al, 1996).
    B) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Exfoliative dermatitis may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus may occur following therapeutic use of methimazole (Prod Info TAPAZOLE(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Pruritus may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia has been reported as an adverse effect of methimazole therapy (Prod Info TAPAZOLE(R) oral tablets, 2012). Arthralgia was reported in 16 out of 194 patients (8.2%) treated with an average methimazole dose of 60 mg/day (Werner et al, 1989). No pattern of rheumatologic disease has been found in these patients. Arthralgias, myalgias, and joint swelling have been reported with relative frequency during carbimazole therapy, although the true incidence of these complications is unknown (Richards, 1999; Hardman et al, 1996; Kampmann & Hansen, 1981). Arthritis syndrome, which is rare, is generally transient, occurring within 2 months of initiation of therapy and resolving within 4 weeks of stopping therapy (Richards, 1999; Bajaj et al, 1998; Hietarinta & Merilahti-Palo, 1989).
    2) WITH POISONING/EXPOSURE
    a) Joint pain may occur following an overdose (Prod Info TAPAZOLE(R) oral tablets, 2012).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia may occur following therapeutic use of methimazole (Prod Info TAPAZOLE(R) oral tablets, 2012).
    C) MYOSITIS
    1) WITH THERAPEUTIC USE
    a) Myositis with pain, weakness, and increased creatine kinase concentrations has been reported with carbimazole (Pasquier et al, 1991; Page & Nussey, 1989).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) Hypothyroidism (symptoms: nausea and vomiting, constipation, headache, drowsiness, coldness, dry and puffy skin, muscle aches) and goiter may occur during therapy with these drugs as a result of chronic excessive dosage (Prod Info TAPAZOLE(R) oral tablets, 2012; Kampmann & Hansen, 1981).
    2) WITH POISONING/EXPOSURE
    a) Clinically significant hypothyroidism is not expected after a single acute overdose because of the short duration of action of these drugs.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) CELL-MEDIATED IMMUNE REACTION
    1) WITH THERAPEUTIC USE
    a) An allergic host reaction, involving lymphocyte sensitization, may result in cholestatic hepatic damage following chronic therapeutic use of carbimazole and methimazole (Bartalena et al, 1996; Vitug & Goldman, 1985; Jenkins & Evans, 1981).
    b) Carbimazole hypersensitivity resulting in the development of antibodies to connective tissue or neural antigens in the cochlea has been reported. Hearing loss and tinnitus resulted (Hill et al, 1994).
    c) Delayed type hypersensitivity reaction to these drugs, resulting in generalized dermatitis, has been reported (Goh & Ng, 1985; van Ketel, 1983).
    B) DISORDER OF IMMUNE FUNCTION
    1) WITH THERAPEUTIC USE
    a) An estimated occurrence of agranulocytosis due to methimazole therapy is between 0.1% and 1%; it most frequently develops within the first 3 months of therapy. Agranulocytosis, an idiosyncratic reaction, may rarely occur and is suspected to be due to an immune-mediated reaction (Breier et al, 2001; O'Doherty, 1999; Escobar-Morreale et al, 1997; Bartalena et al, 1996; Biswas et al, 1991; Werner et al, 1989; Moreb et al, 1983).
    b) Carbimazole-induced immune hemolytic anemia has been reported in a 65-year-old female. An antibody reaction to carbimazole, but not to methimazole, was revealed. The authors suggest that a small, but significant proportion of carbimazole is rapidly bound to RBC membranes and is protected at the molecular sites where hydroxylation to methimazole takes place (Salama et al, 1988).
    c) Insulin autoimmune syndrome has been reported as a rare adverse effect of carbimazole and methimazole, with hypoglycemia and elevated total serum insulin level, free insulin and insulin antibody, and hyperglucagonemia (Hakamata et al, 1995; Matsushita et al, 1994; Lu et al, 1994) .
    d) Methimazole-induced ANCA-associated vasculitis and lupus-like syndrome have been reported following chronic therapy, but this is very rare (Kawachi et al, 1995). Cryofibrinogenemia with polyarthralgia, probably autoantibody-related, has also been reported following chronic methimazole therapy (Hosoi et al, 1997).
    e) Serum sickness has been reported after 3 weeks of therapy with methimazole. Circulating immune complexes were positive. The patient recovered after treatment with prednisolone (van Kuyk et al, 1983).

Reproductive

    3.20.1) SUMMARY
    A) Methimazole is classified as FDA Pregnancy Category D. Methimazole crosses the placental membrane readily and can induce goiter and cretinism in the developing fetus. Congenital defects such as aplasia cutis (manifested by scalp defects), esophageal atresia with tracheoesophageal fistula, and choanal atresia with absent/hypoplastic nipples have occurred rarely in infants exposed to methimazole in utero.
    3.20.2) TERATOGENICITY
    A) SUMMARY
    1) Methimazole crosses the placental membrane readily and can induce goiter and cretinism in the developing fetus. Congenital defects such as aplasia cutis (manifested by scalp defects), esophageal atresia with tracheoesophageal fistula, and choanal atresia with absent/hypoplastic nipples have occurred rarely in infants exposed to methimazole in utero (Prod Info Tapazole(R), methimazole, 2001).
    2) CASE REPORT: Several malformations were observed in a child born to a 33-year-old woman who had received methimazole 30 mg per day and metoprolol 150 mg per day during pregnancy. The birth defects included choanal atresia, esophageal atresia with tracheo-esophageal fistula, omphaloenteric connection and multiple ventricular septal defects (Johnsson et al, 1997).
    3) Esophageal atresia and tracheoesophageal fistula occurred in 2 infants born to hyperthyroid mothers receiving methimazole 30 to 40 mg/day before and during pregnancy. The mothers also received thyroid hormones during the eighth and eighteenth week of gestation, respectively (Ramirez et al, 1992).
    B) APLASIA CUTIS CONGENITA
    1) Aplasia cutis congenita, a congenital absence of skin most commonly limited to the scalp and presenting as a solitary lesion, has rarely been reported in infants born to hyperthyroid mothers taking chronic methimazole, but not taking propylthiouracil (Prod Info Tapazole(R), methimazole, 2001; Bartalena et al, 1996; Vogt et al, 1995; Mandel et al, 1994; Sargent et al, 1994; Farine et al, 1988; van Dijke et al, 1987). A genetic predisposition is possible.
    2) CASE REPORT: Aplasia cutis congenita (ACC) was reported in a male infant exposed to methimazole during the first 10 weeks of pregnancy. A 28-year-old woman with Graves' disease who was taking methimazole 5 mg daily for 3 years, became aware of her pregnancy at 10 weeks gestation. Upon discovery, methimazole was immediately replaced with propylthiouracil 50 mg/day. The patient's thyroid hormone levels and antithyroid antibodies were maintained within normal levels. At 39-weeks gestation, the patient delivered a male infant of normal birth weight and height. The infant had a defect of the scalp on the sagittal line of the parietooccipital region. No other malformations were observed and skull defects were not detected during radiographs. Intracranial lesions were not detected during cranial ultrasonography and the infant's kidney function appeared to be normal. Treatment with povidone-iodine, antibiotic ointment, and rifamycin were initiated in addition to epithelizing and cicatrizing agents. The infant's lesion healed within 6 weeks without any further complications (Akar et al, 2011).
    3) A case of aplasia cutis congenita after exposure to methimazole has been reported. The mother took methimazole 20 to 40 milligrams daily throughout pregnancy (Vogt et al, 1995). The authors suggested that, although the risk is small, there is a causal relationship between aplasia cutis congenita and methimazole administration.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Methimazole is classified as FDA Pregnancy Category D (Prod Info TAPAZOLE(R) tablets, 2004)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Methimazole is distributed into breast milk (Prod Info Tapazole(R), methimazole, 2001). One study found no adverse effects on thyroid function or thyroid hormone levels in breast-fed infants during up to 6 months of maternal treatment with methimazole (Azizi, 1996).

Genotoxicity

    A) Methimazole has been shown to induce sister-chromatid exchanges in lymphocytes from methimazole-induced hypothyroid mice. An interference with normal proliferation of T lymphocytes by suppressing the production of IL-2 was also demonstrated.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor serial CBC with differential with platelet count, renal function, liver enzymes, and thyroid function tests after significant overdose.
    C) Plasma concentrations are not routinely available. Measurement of T3 (triiodothyronine) and reverse T3 (a major metabolite of T4 with no metabolic activity) levels may confirm a history of ingestion, but the clinical significance is unknown.
    4.1.2) SERUM/BLOOD
    A) ENDOCRINE
    1) Carbimazole and methimazole levels are not routinely available. Measurement of T3 (triiodothyronine) and reverse T3 (a major metabolite of T4 with no metabolic activity) levels may confirm a history of ingestion, but the clinical significance is unknown.
    B) HEMATOLOGIC
    1) Agranulocytosis and pancytopenia are immunologic effects of chronic therapy and have not yet been reported following acute overdose. CBC with platelets and differential leukocyte counts may aid in diagnosis. Routine monitoring of the full blood count is not indicated unless the patient is symptomatic (O'Doherty, 1999).
    C) BLOOD/SERUM CHEMISTRY
    1) Hepatic serum enzyme levels may become elevated in overdose cases. Isoenzyme determination is recommended. Elevations in alkaline phosphatase do not necessarily reflect liver toxicity and may be related to increased bone or muscle isoenzyme.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Carbimazole and methimazole can be measured in body fluids with accuracy and in small quantities by gas-liquid chromatography, high performance liquid chromatography and radio-immunoassay (Cooper et al, 1984; Kampmann & Hansen, 1981).
    2) A sensitive and specific radioimmunoassay for methimazole has been developed to study human pharmacokinetics of methimazole in various body fluids. The detection limit is 2.5 ng (22 pmol). No effect of serum proteins on methimazole immuno-activity was reported in this study (Cooper et al, 1984).
    3) Jansson et al (1983, 1985) reported a highly sensitive gas chromatographic-mass spectrometric assay method for the quantification of methimazole in human plasma. A precision of 6% with a detection limit of 5 mcg/L (44.0 nmol/L) was reported (Jansson et al, 1985).
    4) A sensitive spectrophotometric method is described for the determination of methimazole in human plasma. Sensitivity is reported in the range of 0.4 to 4 mcg/mL (Gallo et al, 1983).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with a small inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a large or deliberate overdose, and those who are symptomatic, should be referred to a healthcare facility for evaluation. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serial CBC with differential with platelet count, renal function, liver enzymes, and thyroid function tests after significant overdose.
    C) Plasma concentrations are not routinely available. Measurement of T3 (triiodothyronine) and reverse T3 (a major metabolite of T4 with no metabolic activity) levels may confirm a history of ingestion, but the clinical significance is unknown.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor serial CBC with differential with platelet count, renal function, liver enzymes, and thyroid function tests after significant overdose.
    3) Plasma concentrations are not routinely available. Measurement of T3 (triiodothyronine) and reverse T3 (a major metabolite of T4 with no metabolic activity) levels may confirm a history of ingestion, but the clinical significance is unknown.
    B) NEUTROPENIA
    1) Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), or filgrastim, may be effective in accelerating bone marrow recovery after carbimazole or methimazole therapy. Erythrocyte and platelet transfusions may be necessary. Treatment with these drugs has been shown to significantly shorten recovery time in patients with methimazole-induced agranulocytosis (Magner & Snyder, 1994; Tamai et al, 1993).
    a) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    1) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    2) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    3) Monitor CBC with differential.
    b) Lopez-Karpovitch et al (1992) reported a patient with methimazole-induced severe aplastic anemia who responded well to therapy with recombinant GM-CSF and glucocorticosteroids (Lopez-Karpovitch et al, 1992).
    c) CASE REPORT: A 74-year-old woman developed aplastic anemia 8 weeks after starting methimazole therapy. The patient gradually recovered following discontinuation of methimazole and treatment with G-CSF (a daily dose of 300 micrograms G-CSF subcutaneously between days 2 and 6 of observation), high-dose corticosteroids, antibiotics, and supportive hemotherapy. On day 25, she was discharged in remission (Jakucs & Pocsay, 2006).
    2) ANTIBIOTIC THERAPY
    a) Infection or fever in neutropenic patients should be treated aggressively with antibiotics. Cultures and sensitivities should be done. Appropriate broad-spectrum antibiotics should be initiated before culture results are known. Adjust antibiotic regimen based on culture results.

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) Hemodialysis, peritoneal dialysis, forced diuresis, or charcoal hemoperfusion have not been shown to be beneficial in methimazole overdose (Prod Info TAPAZOLE(R) oral tablet, 2004).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Adverse effects at higher doses (60 mg/day) are common.
    B) THERAPEUTIC DOSE: ADULTS: Initial oral doses range from 15 to 60 mg orally in 3 divided doses every 8 hours daily. Maintenance: 5 to 15 mg orally per day. CHILDREN: Initial oral dose is 0.4 mg/kg/day orally in 3 divided doses every 8 hours daily. Maintenance, one-half of the initial oral dose.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC AGENT
    1) CARBIMAZOLE - Initial oral dosage is 20 to 60 milligrams/day. It may be given in divided doses or once daily. Control of symptoms is achieved in 1 to 2 months. When the patient is euthyroid the dose is gradually reduced to the smallest amount that will maintain the euthyroid state. Typical maintenance doses are 5 to 15 milligrams/day (S Sweetman , 2000).
    2) METHIMAZOLE - Initial oral doses range from 15 to 60 milligrams (mg) (15 mg for mild hyperthyroidism; 30 to 40 mg for moderately severe; 60 mg for severe) orally per day in 3 divided dose at approximately 8-hour intervals. The usual maintenance oral doses are 5 to 15 mg orally per day (Prod Info methimazole oral tablets, 2008).
    3) Methimazole 20 mg is approximately equivalent to carbimazole 30 mg (S Sweetman , 2000).
    7.2.2) PEDIATRIC
    A) SPECIFIC AGENT
    1) CARBIMAZOLE - Administer an initial dose of 250 micrograms per kg body-weight three times daily, adjust dose according to response (S Sweetman , 2000).
    2) METHIMAZOLE - The initial oral dose is 0.4 milligram (mg)/kilogram/day orally in 3 divided doses at approximately 8-hour intervals; maintenance doses are approximately one-half the initial dose (Prod Info methimazole oral tablets, 2008).

Maximum Tolerated Exposure

    A) Overdoses have not been reported. Adverse effects at higher doses (60 mg/day) are common. Jorde et al (1995) reported adverse effects at higher doses resulting in discontinuation of drug to include skin rashes, arthralgia and agranulocytosis (Jorde et al, 1995).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) METHIMAZOLE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 500 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 860 mg/kg (RTECS , 2001)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 345 mg/kg (RTECS , 2001)
    4) LD50- (ORAL)RAT:
    a) 2250 mg/kg (RTECS , 2001)
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 1050 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Methimazole, a thyroid hormone synthesis inhibitor, is used in the treatment of hyperthyroidism. Its actions are similar to propylthiouracil although it does not inactivate the existing thyroxine and triiodothyronine stored in the thyroid or in the blood (Prod Info TAPAZOLE(R) oral tablet, 2004).
    B) Carbimazole is a derivative of methimazole, and differs from methimazole only by the presence of a carbethoxy group bound to a ring nitrogen atom (Hardman et al, 1996). The drug was developed with expectations of producing a longer duration of action than methimazole. However, plasma concentration curves following oral administration of carbimazole have been nearly identical to those achieved with oral methimazole, not supporting this assumption (Jansson et al, 1983). Carbimazole is a prodrug, with all clinical activity in hyperthyroid patients being attributable to methimazole; rapid and total conversion to methimazole occurs.
    C) The mechanism of action of thioamide derivatives in hyperthyroidism is via inhibition of the formation of thyroid hormones. Specifically, these agents inhibit incorporation of iodide into tyrosyl residues of thyroglobulin; the coupling of iodotyrosyl residues to form iodothyronines is also inhibited (Prod Info Tapazole(R), methimazole, 2001; Hardman et al, 1996). The thioamides do not inactivate or interfere with release of previously formed thyroid hormones that are stored in the thyroid gland. No permanent effect on the thyroid gland is observed with the use of these agents. Unlike methimazole and carbimazole, propylthiouracil inhibits the peripheral conversion of thyroxine to triiodothyronine (Kampmann & Hansen, 1981).

Toxicologic Mechanism

    A) IMMUNE-RELATED MECHANISMS: It has been suggested that methimazole and propylthiouracil do not have cross-reactivity to each other in regards to adverse effects. Following treatment with methimazole, antinuclear and anti-DNA antibodies have become positive in a significant number of cases with adverse effects to treatment. An immunological mechanism may be responsible for adverse effects rather than accumulating or direct toxic effects (Nakakshima et al, 1982). Werner et al (1989) found no relationship between adverse effects and thyroid autoantibodies titers. Adverse effects to these drugs are similar in both high- and low-dose regimens.
    1) LIVER TOXICITY: Unpredictable adverse liver changes following treatment with these drugs is most likely due to hypersensitivity (Moreno Sanchez et al, 1989). Bone marrow aplasia following therapy with these drugs is most likely due to an effect on the immune system via indirect inhibition of thyroid cell activity. Agranulocytosis may also be an autoimmune phenomenon in which lymphocytes have been sensitized to methimazole (Breier et al, 2001).
    B) HYPOPROTHROMBINEMIA: The mechanism of this rare event is the inhibition of the vitamin K dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid. Methimazole also inhibits vitamin K epoxide reductase (Lipsky & Gallego, 1988).

Physicochemical

Physical Characteristics

    A) CARBIMAZOLE is a white or yellowish-white crystalline powder. It is slightly soluble in water; soluble in alcohol and in acetone (S Sweetman , 2000).
    B) METHIMAZOLE is a white to pale buff crystalline powder having a faint characteristic odor. Solubility is 1 in 5 parts of water and 1 in 5 parts of alcohol (S Sweetman , 2000).

Ph

    A) METHIMAZOLE - Aqueous solutions are practically neutral to litmus (S Sweetman , 2000).

Molecular Weight

    A) CARBIMAZOLE: 186.2 (S Sweetman , 2000)
    B) METHIMAZOLE: 114.2 (S Sweetman , 2000)

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